ABSTRACT The central premise of our program is that durable control of HIV in the absence of antiretroviral therapy (?remission?) will require the generation of de novo potent and sustained HIV-specific CD8+ cell responses that target evolutionarily conserved epitopes. Our program is inspired by the recent success of VGX-3100 (Inovio), a DNA therapeutic vaccine for HPV that leads to histopathologic regression of pre-malignant lesions in people and is associated with a potent, sustained boost to HPV-specific CD8+ T cell populations. A closely related multi-clade gag/pol/env DNA vaccine (PENNVAX, Inovio) has been studied for HIV prevention and is known to be both safe and highly immunogenic. The therapeutic potential of this novel approach is unknown and will be the focus of our work in the first two years. We are fully aware, however, that administration of a DNA vaccine alone (PENNVAX-GP) will unlikely be sufficient to achieve a disease remission. The presence of pre-existing escape mutations and immune dysregulation known to persist during treated HIV disease will hamper vaccine effectiveness, and adjuvant approaches will be likely be needed. In the first two years, we will determine if IL- 12 can enhance immunogenicity of this vaccine. This work is based on extensive experience in non-human primates and in HIV-uninfected adults showing IL-12 enhances immunogenicity of DNA vaccines. In Years 3 to 5, we will determine if PD-1 blockade with pembrolizumab (Merck) enhances vaccine effectiveness. This study will likely test for the first time if PD-1 blockade during active vaccination improves the breadth of the immune response and increases the numbers of effector cells. Our study will leverage the considerable strengths of our established multi-disciplinary research team to pursue highly innovative approaches to measuring vaccine immunogenicity and the viral reservoir. Should we be successful, we will have at the end of this program a viable vaccine strategy that has a manageable safety profile and is known to be highly immunogenic.